Can a Form Letter from FDA "Blow Your Mind"?

Adam Feuerstein appears to be a generally astute observer of the biotech scene. As a finance writer, he's accosted daily with egregiously hyped claims from small drug companies and their investors, and I think he tends to do an excellent job of spotting cases where breathless excitement is unaccompanied by substantive information.

However, Feuerstein's healthy skepticism seems to have abandoned him last year in the case of a biotech called Sarepta Therapeutics, who released some highly promising - but also incredibly limited - data on their treatment for Duchenne muscular dystrophy. After a disappointing interaction with the FDA, Sarepta's stock dropped, and Feuerstein appeared to realize that he'd lost some objectivity on the topic.

However, with the new year comes new optimism, and Feuerstein seems to be back to squinting hard at tea leaves - this time in the case of a form letter from the FDA.

He claims that the contents of the letter will "blow your mind". To him, the key passage is:

We understand that you feel that eteplirsen is highly effective, and may be confused by what you have read or heard about FDA's actions on eteplirsen. Unfortunately, the information reported in the press or discussed in blogs does not necessarily reflect FDA's position. FDA has reached no conclusions about the possibility of using accelerated approval for any new drug for the treatment of Duchenne muscular dystrophy, and for eteplirsen in particular.

Feuerstein appears to think that the fact that FDA "has reached no conclusions" may mean that it may be "changing its mind". To which he adds: "Wow!"

Adam Feuerstein: This time,
too much froth, not enough coffee?

I'm not sure why he thinks that. As far as I can tell, the FDA will never reach a conclusion like this before its gone through the actual review process. After all, if FDA already knows the answer before the full review, what would the point of the review even be? It would seem a tremendous waste of agency resources. Not to mention how non-level the playing field would be if some companies were given early yes/no decisions while others had to go through a full review.

It seems fair to ask: is this a substantive change by FDA review teams, or would it be their standard response to any speculation about whether and how they would approve or reject a new drug submission? Can Feuerstein point to other cases where FDA has given a definitive yes or no on an application before the application was ever filed? I suspect not, but am open to seeing examples.

A more plausible theory for this letter is that the FDA is attempting a bit of damage control. It is not permitted to share anything specific it said or wrote to Sarepta about the drug, and has come under some serious criticism for “rejecting” Sarepta’s Accelerated Approval submission. The agency has been sensitive to the DMD community, even going so far as to have Janet Woodcock and Bob Temple meet with DMD parents and advocates last February. Sarepta has effectively positioned FDA as the reason for it’s delay in approval, but no letters have actually been published, so the conversation has been a bit one-sided. This letter appears to be an attempt at balancing perspectives a bit, although the FDA is still hamstrung by its restriction on relating any specific communications.

Ultimately, this is a form letter that contains no new information: FDA has reached no conclusions because FDA is not permitted to reach conclusions until it has completed a fair and thorough review, which won't happen until the drug is actually submitted for approval.

We talk about "transparency" in terms of releasing clinical trials data, but to me there is a great case to be made for increase regulatory transparency. The benefits to routine publication of most FDA correspondence and meeting results (including such things as Complete Response letters, explaining FDA's thinking when it rejects new applications) would actually go a long way towards improving public understanding of the drug review and approval process.

The Case against Randomized Trials is, Fittingly, Anecdotal

I have a lot of respect for Eric Topol, and am a huge fan of his ongoing work to bring new mobile technology to benefit patients.

The Trial of the Future

However, I am simply baffled by this short video he recently posted on his Medscape blog. In it, he argues against the continued use of randomized controlled trials (RCTs) to provide evidence for or against new drugs.

His argument for this is two anecdotes: one negative, one positive. The negative anecdote is about the recently approved drug for melanoma, Zelboraf:

Well, that's great if one can do [RCTs], but often we're talking about needing thousands, if not tens of thousands, of patients for these types of clinical trials. And things are changing so fast with respect to medicine and, for example, genomically guided interventions that it's going to become increasingly difficult to justify these very large clinical trials. 

For example, there was a drug trial for melanoma and the mutation of BRAF, which is the gene that is found in about 60% of people with malignant melanoma. When that trial was done, there was a placebo control, and there was a big ethical charge asking whether it is justifiable to have a body count. This was a matched drug for the biology underpinning metastatic melanoma, which is essentially a fatal condition within 1 year, and researchers were giving some individuals a placebo.

First and foremost, this is simply factually incorrect on a couple extremely important points.

1. Zelboraf was not approved based on any placebo-controlled trials. The phase 1 and phase 2 trials were both single-arm, open label studies. The only phase 3 trial run before FDA approval used dacarbazine in the comparator arm. In fact, of the 34 trials currently listed for Zelboraf on ClinicalTrials.gov, only one has a placebo control: it’s an adjuvant trial for patients whose melanoma has been completely resected, where no treatment may very well be the best option.
2. The Zelboraf trials are not an example of “needing thousands, if not tens of thousands, of patients” for approval. The phase 3 trial enrolled 675 patients. Even adding the phase 1 and 2 trials doesn’t get us to 1000 patients.

Correcting these details take a lot away from the power of this single drug to be a good example of why we should stop using “the sanctimonious [sic] randomized, placebo-controlled clinical trial”.

The second anecdote is about a novel Alzheimer’s Disease candidate:

A remarkable example of a trial of the future was announced in May. For this trial, the National Institutes of Health is working with [Banner Alzheimer's Institute] in Arizona, the University of Antioquia in Colombia, and Genentech to have a specific mutation studied in a large extended family living in the country of Colombia in South America. There is a family of 8000 individuals who have the so-called Paisa mutation, a presenilin gene mutation, which results in every member of this family developing dementia in their 40s. 

Researchers will be testing a drug that binds amyloid, a monoclonal antibody, in just 300 family members. They're not following these patients out to the point of where they get dementia. Instead, they are using surrogate markers to see whether or not the process of developing Alzheimer's can be blocked using this drug. This is an exciting way in which we can study treatments that can potentially prevent Alzheimer's in a very well-demarcated, very restricted population with a genetic defect, and then branch out to a much broader population of people who are at risk for Alzheimer's. These are the types of trials of the future. 

There are some additional disturbing factual errors here – the extended family numbers about 5,000, not 8,000. And estimates of the prevalence of the mutation within that family appear to vary from about one-third to one-half, so it’s simply wrong to state that “every member of this family” will develop dementia.

However, those errors are relatively minor, and are completely overshadowed by the massive irony that this is a randomized, placebo-controlled trial. Only 100 of the 300 trial participants will receive the active study drug, crenezumab. The other 200 will be on placebo.

And so, the “trial of the future” held up as a way to get us out of using randomized, placebo-controlled trials is actually a randomized, placebo-controlled trial itself. I hope you can understand why I’m completely baffled that Topol thinks this is evidence of anything.

Finally, I have to ask: how is this the trial of the future, anyway? It is a short-term study on a highly-selected patient population with a specific genetic profile, measuring surrogate markers to provide proof of concept for later, larger studies. Is it just me, or does that sound exactly like the early lovastatin trials of the mid-1980’s, which tested cholesterol reduction in a small population of patients with severe heterozygous familial hypercholesterolemia? Back to the Future, indeed.


[Image: time-travelling supercar courtesy of Flickr user JoshBerglund19.]

Changing the Rules, Ever So Slightly, For Rare Diseases

At the end of last year, US Reps Cliff Stearns (R-FL) and Ed Towns (D-NY) introduced the Unlocking Lifesaving Treatments for Rare-Diseases Act (ULTRA for short). Despite what its bold name might imply (and unlike many recent congressional healthcare bills), ULTRA is actually a modest and carefully-though-out piece of legislation.

The main thrust of ULTRA is to enable developers of drugs for rare diseases to take advantage of the FDA’s existing Accelerated Approval pathway. Accelerated Approval reduces the initial burden of proof for manufacturers to bring a drug to market by conducting smaller clinical trials that measure a drug’s efficacy against “surrogate” endpoints – that is, endpoints that do not directly measure the disease, but rather other factors that are associated with the disease. This can greatly reduce the time and cost of clinical trials.

To qualify for Accelerated Approval, however, trials for a new drug needs to meet two conditions:

• The drug must be studied for treatment of a serious disease, with unmet medical need


• There must be clinical evidence that improving the surrogate endpoint is reasonably likely to predict real benefit for those with the disease

ULTRA does not change the first criterion, only the second. For rare diseases, there is often not robust clinical evidence to support surrogate endpoints, so the bill alters the language slightly to permit the FDA to accept “reasonable scientific data that support and qualify the relevance of the surrogate endpoint”. In essence, the burden to prove the validity of the surrogate has been relaxed, permitting their use in pivotal trials, and using a surrogate may reduce the number of patients needed for a trial by as much as 50-75%.

Accelerated Approval still requires the drug manufacturer to complete full trials to more firmly establish the drug’s efficacy – it just allows the drug to be available on the market while those full trials are being conducted. ULTRA does not change this requirement for drugs of rare diseases, so in the end it is not lowering the standard for these drugs at all.

Obviously, anything can happen to a bill as it wends its way through congress. But as it is currently written, ULTRA is a highly rational, well-targeted adjustment to current law that should quickly show benefits for patients with rare diseases, and deserves quick action and passage.

(Further reading: the FDA Law Blog has an excellent review of the proposed act.)